Several processes for the preparation of allopregnanolone are known in the literature. The conversion of 3β-hydroxy-5α-pregnan-20-one (isopregnanolone) into 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) through Mitsunobu reaction and subsequent basic hydrolysis is described, for example, in J. Med. Chem. 1990, 33, 1572-1581. However, the resultant product must undergo a laborious purification phase consisting of crystallization from ethyl acetate/aqueous ethanol, column chromatography with 2% acetone in dichloromethane and, finally, crystallization from aqueous ethanol.
International patent application WO 2009/108804 describes a process consisting of the catalytic hydrogenation of pregnenolone to give isopregnanolone, purified by crystallization from hexane/ethyl acetate, which is then subjected to Mitsunobu reaction and hydrolysis to yield allopregnanolone, purified by column chromatography with ethyl acetate in hexane (0-35%).
Finally, in Collect. Czech. Chem. Commun. 2009, 74, 643-650, the conversion of isopregnanolone into the formic ester of allopregnanolone through Mitsunobu reaction is described. The resultant ester intermediate is subjected to column chromatography in petroleum ether/acetone (98:2) and, subsequently, to crystallization from acetone. After basic hydrolysis, allopregnanolone is purified by crystallization from acetone/ethyl acetate.
All the processes known in the art foresee a laborious purification phase which includes the use of at least one chromatography and/or chromatography followed by crystallization. Furthermore, the purification of allopregnanolone according to the crystallizations known in the art does not allow to efficaciously remove impurities and reaction byproducts.
However, since the product is for the use in therapy, a process which allows to obtain allopregnanolone with a purity of pharmaceutical grade and, at the same time, which is of easy industrial applicability is required.
Therefore, there is still the need of an improved process for the preparation of allopregnanolone which overcomes all the drawbacks of the known processes. In particular, there is the need of an improved method for the purification of allopregnanolone, for example, a method which does not foresee any laborious multistep purification and/or the use of chromatography, which is not time consuming, expensive and disadvantageous with respect to the yield.